This project was designed to assess in detail the structural, ultrastructural, and pharmacological correlates and prerequisites of nerve cell degeneration caused by excitotoxic amino acid. Because of its layered structure, defined neuronal populations, and distinct glutamate-containing fiber systems, the hippocampal formation of the rat will be employed. In vivo experiments will evaluate the effects of lesions and drugs on the neurotoxicity of three excitotoxic amino acids; namely, kainic, ibotenic, and glutamic acids. The drugs used in this study, morphine, naloxone, diazepam, gamma-Aminoadipic acid, and amino acid esters, have been shown previously to enhance or block neurotoxicity. Information derived from the in vivo experiments will then be scrutinized in organotypic cultures of rat hippocampus. Ultrastructural studies in the tissue cultures are expected to add substantially to our understanding of the in vivo situation. In particular, the involvement of dendritic spines in the initiation and propagation of the degenerative process will be investigated. Finally, new knowledge gained from the easily accessible in vitro system will be applied for ultrastructural evaluation in the whole animal. Since excitotoxic amino acids may play an integral role in the etiology of neurodegenerative disorders like Huntington's disease, detailed understanding of the basic mechanism associated with specific nerve cell death may give new information toward development of preventive measures.